EPHB4 Receptor Kinase as a Target in Prostate Cancer

EPHB4 受体激酶作为前列腺癌的靶点

• 批准号: 8932478
• 负责人: Sarki A. Abdulkadir
• 金额: $ 27.49万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-18 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8932478
• 关键词: 1-Phosphatidylinositol 3-Kinase; Androgen Antagonists; Androgen Receptor; Androgens; Apoptosis; Cancer Patient; Castration; Cell Survival; Cessation of life; Chimeric Proteins; Clinical; Clinical Research; Clinical Trials; Complex; Data; Development; Disease; Disease Progression; Dose-Limiting; Eph Family Receptors; EphB4 Receptor; Ephrin-B2; Epidermal Growth Factor Receptor; Generations; Genes; Genetic; Gleason Grade for Prostate Cancer; Human; IGF1R gene; Knockout Mice; Lead; Ligands; MAP Kinase Gene; Malignant Neoplasms; Malignant neoplasm of prostate; Modality; Modeling; Molecular; Mus; Mutation; Neoplasm Metastasis; Oncogenes; PI3K/AKT; PTEN gene; Pathway interactions; Patients; Phosphotransferases; Play; Pre-Clinical Model; Prostate; Prostatic Neoplasms; Protein Tyrosine Kinase; Proto-Oncogene Proteins c-akt; Receptor Protein-Tyrosine Kinases; Recurrence; Refractory; Relapse; Resistance; Role; Safety; Sampling; Serum Albumin; Signal Pathway; Signal Transduction; TP53 gene; Testing; Therapeutic; Time; Toxic effect; Transgenic Mice; Transgenic Organisms; Translations; Treatment Efficacy; Tumor Suppressor Proteins; Xenograft Model; Xenograft procedure; abiraterone; abstracting; angiogenesis; cancer recurrence; castration resistant prostate cancer; cell motility; clinically relevant; cohort; deprivation; high risk; inhibitor/antagonist; men; mouse model; neoplastic cell; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; overexpression; phase 1 study; phase II trial; pre-clinical; prostate cancer cell; prostate cancer model; prostate carcinogenesis; receptor; receptor expression; resistance mechanism; targeted treatment; therapeutic target; therapy development; therapy resistant; tumor; tumor progression; tumor xenograft

PROJECT 3: PROJECT SUMMARY/ABSTRACT A major clinical problem in the management of prostate cancer is the difficulty associated with treating aggressive cancers, especially those that are highly castration resistant. The androgen signaling pathway remains a key therapeutic target for advanced prostate cancer but resistance to agents targeting this pathway is common, highlighting the need to develop novel therapeutic approaches. Mouse prostate cancer modeling has elucidated molecular pathways of aggressive, castration-resistant prostate cancer (CRPC) which include loss of the tumor suppressors PTEN and TP53 and overexpression of the MYC oncogene. Using these spontaneous mouse models of prostate cancer we have identified Ephrin receptor EphB4 as a potential therapeutic target. EPHB4 is a receptor tyrosine kinase that with its ligand ephrin B2, are not expressed in normal prostate gland, but are expressed in a majority of human prostate cancers. EPHB4 is induced by multiple pathways important for CRPC development, including loss of PTEN and TP53 as well as activation of the PI3K pathway downstream of EGFR and IGF1R. In turn, EPHB4 activation engages multiple signaling pathways, including the PI3 kinase/AKT and MAPK pathways known to modulate the androgen receptor and drive CRPC development. To test the significance of EphB4, we generated conditional EphB4 knockout mouse. We found that genetic deletion of EphB4 or its inhibition using a soluble antagonist (sEPHB4) profoundly inhibited prostate tumorigenesis driven by loss of Pten and led to the regression of established tumors in transgenic mice. This was associated with inhibition of PI3K/AKT signaling and apoptosis. Notably, sEpBh4 antagonist and EphB4 knockdown led to markedly lower levels of androgen receptor (AR) protein. These functional genetic data lead us to hypothesize that EPHB4 is a novel pharmacologic target with high therapeutic potential in prostate cancer, including CRPC. We will explore this hypothesis by targeting EphB4 in genetically complex mouse models (loss of Pten, Tp53 and Myc over-expression) and human xenograft models of prostate cancer and CRPC, singly or in combination with AR-targeted therapy (including enzalutamide, abiraterone). We will examine human prostate tumor samples including metastases and CRPCs for the expression of EphB4, EphrinB2, and downstream markers. A soluble decoy EPHB4 receptor – human serum albumin fusion protein (sEPHB4HSA) antagonist is in early human trials in other tumors, and has been found to be remarkably safe in Phase I study. We will therefore implement a feasibility clinical trial of sEPHB4HSA aimed at determining the therapeutic efficacy of targeting EPHB4 in men with CRPC. Successful completion of the preclinical and early clinical studies we propose in this application could lead to a rapid translation of soluble EPHB4 antagonist as a treatment for advanced prostate cancer.

项目3：项目摘要/摘要 前列腺癌管理中的一个主要临床问题是与​​治疗侵略性有关的困难 癌症，尤其是那些高度cast割的癌症。雄激素信号通路仍然是关键 晚期前列腺癌的治疗靶标，但针对该途径的药物的耐药性很常见， 强调开发新型治疗方法的必要性。小鼠前列腺癌建模已阐明 侵略性，耐castration抗性前列腺癌（CRPC）的分子途径，包括肿瘤的丧失 促进pten和tp53以及迈克癌基因的过表达。使用这些自发鼠标 前列腺癌的模型我们已经将Ephrin受体EPHB4确定为潜在的治疗靶点。 ephb4是 具有伴有ephrin b2的受体酪氨酸激酶未在正常的前列腺中表达，而是 在大多数人类前列腺癌中表达。 EPHB4由CRPC重要的多种途径诱导 开发，包括损失PTEN和TP53以及EGFR下游的PI3K途径的激活 和IGF1R。反过 MAPK途径已知可以调节雄激素受体并驱动CRPC的发展。测试 EPHB4的意义，我们产生了条件EPHB4基因敲除小鼠。我们发现遗传缺失的 EPHB4或使用固体拮抗剂（SEPHB4）的抑制作用深刻抑制前列腺肿瘤发生驱动驱动 通过失去PTEN并导致转基因小鼠已建立的肿瘤的消退。这与 抑制PI3K/AKT信号传导和凋亡。值得注意的是，SepbH4拮抗剂和EPHB4敲低导致 明显较低的雄激素受体（AR）蛋白。这些功能性遗传数据导致我们假设 EPHB4是一个新型的药理学靶标，在包括CRPC在内的前列腺癌中具有很高的治疗潜力。 我们将通过针对一般复杂的小鼠模型中的EPHB4来探讨这一假设（PTEN的丢失，TP53 和MYC的过表达）和前列腺癌和CRPC的人异种移植模型，单独或组合 采用靶向AR靶向疗法（包括enzalutamide，abiraterone）。我们将检查人类前列腺肿瘤样品 包括用于表达Ephb4，Ephrinb2和下游标记的转移和CRPC。可溶性 诱饵EPHB4受体 - 人血清白蛋白融合蛋白（SEPHB4HSA）拮抗剂在人类早期试验中 在其他肿瘤中，发现在I期研究中非常安全。因此，我们将实施一个 SEPHB4HSA的可行性临床试验旨在确定男性靶向EPHB4的治疗效率 与CRPC。我们在本应用中提出的临床前和早期临床研究的成功完成 可能导致固体EPHB4拮抗剂的快速翻译作为晚期前列腺癌的治疗方法。